HEM-protein regulates cell migration and asymmetric cell division during development of the ventral nerve cord in Drosophila melanogaster

Abstract

Cell migration and asymmetric cell division are two of the key events during development of the nervous system. I have focused on a typical neuronal lineage, NB4-2→GMC-1→RP2/sib, in the ventral nerve cord (VNC) of the Drosophila embryo to investigate the regulation of neuronal migration and asymmetric cell division during development of the nervous system. I have discovered a migration defect of RP2 neurons in HEM-protein (Hem) mutants: RP2 neurons cross the midline and migrate from the initial hemi-segment to the opposite hemi-segment. The same migration defect is observed in WASP-family verprolin-homologous protein (WAVE/SCAR) and Abl tyrosine kinase (Abl) mutants, suggesting that these three genes might act together to regulate neuronal migration in the VNC. I have found that Hem is required for maintaining the protein level of WAVE in vivo and is necessary for its proper localization in the cell. In Hem mutants, WAVE is down regulated and mis-localized in RP2 neurons, resulting in the migration defect of RP2 neurons. Abl on the other hand negatively regulates the protein level of WAVE. When Abl is ectopically expressed, WAVE protein is down regulated. In Abl mutants, WAVE is up regulated and its hyperactivity may be responsible for the migration defect of RP2 neurons. Meanwhile, instead of asymmetric division in wild type embryos, a symmetric division of GMC-1 is observed in the “strong phenotype embryo†of HemJ4-48 mutants. It was not observed in other Hem mutants and Hem deficiency alleles. The truncated Hem protein (∆HemJ4-48) in HemJ4-48 allele may behave as a neomorphic protein, resulting in the symmetric division of GMC-1. In HemJ4-48 mutants, the apical localization of Inscuteable (Insc) is disrupted, suggesting that regulation of the asymmetric division of GMC-1 by Hem is mediated by Insc. The same symmetric division of GMC-1s was also observed in Abl mutants but not WAVE mutants, suggesting that Abl may act together with Hem to regulate the asymmetric division of GMC-1s. This study uses the Drosophila VNC as a model system and describes how neuronal migration and asymmetric cell division are regulated by Hem during development of the nervous system.